The work of the LBS is directed towards elucidating the mechanisms of lymphomagenesis and progression in aggressive B cell non-Hodgkin's lymphoma in order to improve present therapeutic approaches and to develop novel approaches targeted to genetic lesions present only in tumor cells. Since 1989 we have employed a short duration intensive protocol for the treatment of B cell lymphomas (NHL) in children and small non-cleaved cell lymphomas in adults less than 60 years of age. Over 75 patients have been entered on study to date; event free survival is 90% with a median follow up of 3 years. Results and toxicity in children and adults are similar. This represents an approximate 3.5% improvement over the previous protocol. We have also demonstrated that p53 mutations, present in approximately 40% of tumors, is a significant determinant of prognosis with some, but not other treatment protocols. Future treatment approaches will utilize this and other relevant information in stratifying patients for chemotherapy. A variable fraction of pediatric B cell NHL (20-95% in various world regions) is associated with Epstein Barr virus (EBV). Our studies on pathogenesis have been focused on attempting to dissect the molecular pathways that are dysregulated by EBV. Since only one EBV latent gene, EBNA-1, is invariably expressed in EBV associated tumors; this gene is therefore the likeliest candidate for a role in the maintenance of the malignant phenotype. Analysis of EBNA-1 sequences have revealed tumor-specific mutations. We have also shown that EBNA-1 is able to transactivate the c-myc gene. Finally, we have utilized the transactivating properties of EBNA-1 to specifically target therapy to EBV-containing cells using either a prodrug converting enzyme, or the EBV gene, Zta, which induces EBV replication and cell lysis. In both systems, cell death is confined to EBV containing cells, either when exposed to the prodrug, or via induction of the viral lytic cycle. The second system both requires no drugs, and creates two levels of specificity since both induction and tumoricidal mechanism are dependent upon the presence of EBV. HIV associated work, 10%.